PXD010606-2

PXD010606 is an original dataset announced via ProteomeXchange.

Title	Delineating the role of cooperativity in the design of potent PROTACs for BTK
Description	Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that simultaneously bind to a target protein and an E3 ligase, thereby leading to ubiquitination and subsequent degradation of the target. They present an exciting opportunity to modulate proteins in a manner independent of enzymatic or signaling activity. As such, they have recently emerged as an attractive mechanism to explore previously “undruggable” targets. Despite this interest, fundamental questions remain regarding the parameters most critical for achieving potency and selectivity. Here we employ a series of biochemical and cellular techniques to investigate requirements for efficient knockdown of Bruton’s tyrosine kinase (BTK), a nonreceptor tyrosine kinase essential for B cell maturation. Members of an 11-compound PROTAC library were investigated for their ability to form binary and ternary complexes with BTK and cereblon (CRBN, an E3 ligase component). Results were extended to measure effects on BTK–CRBN cooperative interactions as well as in vitro and in vivo BTK degradation. Our data show that alleviation of steric clashes between BTK and CRBN by modulating PROTAC linker length within this chemical series allows potent BTK degradation in the absence of thermodynamic cooperativity
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_04:47:53.529.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	chuong nguyen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606; scientific name: Rattus rattus (Black rat); NCBI TaxID: 10117;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	LTQ Orbitrap

Revision	Datetime	Status	ChangeLog Entry
0	2018-07-30 02:01:06	ID requested
1	2018-07-31 03:35:31	announced
⏵ 2	2024-10-22 04:47:55	announced	2024-10-22: Updated project metadata.

10.1073/pnas.1803662115;

Zorba A, Nguyen C, Xu Y, Starr J, Borzilleri K, Smith J, Zhu H, Farley KA, Ding W, Schiemer J, Feng X, Chang JS, Uccello DP, Young JA, Garcia-Irrizary CN, Czabaniuk L, Schuff B, Oliver R, Montgomery J, Hayward MM, Coe J, Chen J, Niosi M, Luthra S, Shah JC, El-Kattan A, Qiu X, West GM, Noe MC, Shanmugasundaram V, Gilbert AM, Brown MF, Calabrese MF, Delineating the role of cooperativity in the design of potent PROTACs for BTK. Proc Natl Acad Sci U S A, 115(31):E7285-E7292(2018) [pubmed]

curator keyword: Technical

submitter keyword: Tandem Mass Tag (TMT), Bruton’s tyrosine kinase (BTK), quantitative proteomics,Proteolysis targeting chimera (PROTAC)

CHUONG NGUYEN
contact affiliation	Pfizer, INC.
contact email	chuong.nguyen@pfizer.com
lab head
chuong nguyen
contact affiliation	Pfizer
contact email	chuong.nguyen@pfizer.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD010606
     1. Label: PRIDE project
     2. Name: Delineating the role of cooperativity in the design of potent PROTACs for BTK